Incidence of Dementia Before Age 65 Years Among World Trade Center Attack Responders

Key Points Question Is there an association between occupational exposures while responding to the World Trade Center disaster and the incidence of dementia before 65 years of age? Findings In this cohort study including 5010 World Trade Center general responders aged a median of 53 years at initial assessment, the incidence of dementia before age 65 years was higher in responders who were more severely exposed. Compared with minimally exposed responders who reported no dust exposure or used personal protective equipment, responders working on the pile of debris who reported severe exposures to dust had a higher incidence of dementia before age 65 years even after adjusting for demographic, medical, and social factors. Meaning Disasters often require an emergent response in dangerous conditions, but reliable use of PPE might help prevent the onset of dementia before age 65 years among individuals exposed to an uncontrolled building collapse.

eMethods.eFigure 1. Age-specific incidence rates stratified by five-year age group at baseline for responders in this analysis eTable 1. Selection bias analyses showing association between all covariates and the risk of missing cognitive assessment at baseline, a second follow-up assessment, and genetic information eAppendix 1. Validation effort using a secondary neural network risk scoring metric eFigure 2. Learning curves indicating the artificial neural network's ability to rely on exposure information to identify individuals with dementia in training and testing eFigure 3. Nelson-Aalen plot and accompanying risk table showing cumulative hazards of dementia before age 65 years in World Trade Center responders, stratified by probable exposure severity as determined using a combination of human and computer-driven scoring methods for probable exposures while working on-site in the aftermath of the terrorist attacks of 9/11/2001 eTable 2. Unadjusted and multi-variable adjusted hazard ratios examining incidence of dementia in World Trade Center responders, stratified by exposure severity eAppendix 2. Supplemental analyses eFigure 4. Bar graph showing hazards ratios for early-onset dementia by level of exposure after adjusting for age and family history of amyotrophic lateral sclerosis, Huntington's disease, spinocerebral ataxia, or multisystem atrophy eTable 3. Sensitivity analyses showing trend-level associations between qualitative exposure metric and hazards of early-onset dementia when adjusting for additional covariates that were only available in a subset of individuals eFigure 5. Nelson-Aalen plot and accompanying risk table showing cumulative hazards of dementia before age 65 years in minimally exposed World Trade Center responders, stratified by whether a person report no significant dust exposure or usually wore personal protective equipment as compared to those in low-risk activities while working on-site in the aftermath of the terrorist attacks of 9/11/2001 eReferences.
This supplementary material has been provided by the authors to give readers additional information about their work.

Power Analysis
We expected a twofold increase in the incidence of dementia in responders aged ≤65.
Based on expectations, a power analysis suggested that with an expected observational period of up to five years, we would need approximately 55 new cases of dementia to detect an unadjusted hazard ratio of 2.7.A sample size of 5,000 responders was considered sufficient to provide power to detect a 2.7-fold difference after adjusting for covariates and attrition, and a timeline for data collection was generated that resulted in the present analysis of 5,010 responders over five years whose follow-up information was recorded by 12/31/2022.

Missing Data
Most missing data in this study emerge from people refusing to complete the cognitive assessments, which may be due to the risk of being diagnosed with a potentially stigmatizing diagnosis.To account for this unique type of missing information, we implemented a weighting method first reported in studies of infectious disease that works by leveraging variability in successful research engagement 1,2 .This method then suggests relying on Probit regression to estimate the probability of cognitive assessment completion based on the recruiter success rate and incorporate the probability of study recruitment in covariate adjustment.
From covariates, many of which are asked multiple times over the course of a longitudinal study, we were missing information for 16 potential participants.Sensitivity analyses to examine the importance of including or excluding these individuals found that excluding them did little to change either the incidence rate and did not change the risk associated with

eAppendix 1. Validation effort using a secondary neural network risk scoring metric
We were concerned by the potential that we would misattribute the most severe risks because they may either be relatively innocuous for responders or might either have unanticipated, nonlinear effects or may have effects that were subject to moderation.We therefore not only relied on results from our expert-rated scores shown above to assess severe risk, but also examined a computer-assisted approach that used a neural network to examine prevalent cases of disease, which were excluded from this study.The neural network is a backpropagation network with two hidden layers each consisting of ten synapses each, alongside

eAppendix 2. Supplemental analyses
While not available for everyone because of a delay in its inclusion in the study, a detailed family history was collected indicating the presence of any cognitively impairing disease including all-cause and cause-specific dementia was reported by a subset of WTC responders after its addition to the research program.A family history of all-cause dementia was not associated with exposure ( 2 = 0.245, P=0.993) and therefore does not satisfy a central criterion for confounding.A family history of all-cause dementia was also not associated with a higher incidence of dementia in this study (HR = 0.90 [0.65-1.25],P = 0.528).When entered in a multivariable-adjusted statistical model these variables did not explain the trend attributed to higher exposure as noted by small differences between models, so we did not integrate these analyses into the reported study.The sensitivity of the presented models to analytic decisions was a question of intense interest to research staff.We began by adjusting simply for markers of familial vulnerability to the disease by adjusting for, in subset analyses, family history and possession of the apolipoprotein-e4 allele.Next, we examined whether stratification by age of onset changed results.We considered the necessity of adjusting for COVID diagnostic status as a time-varying covariate; while COVID is ever present, there is no evidence that infection or infection severity is associated with WTC exposures nor that COVID causes dementia in young healthy people.
Nevertheless, we examined the necessity of considering COVID because of its outsized influence on daily life during this period.Next, we considered the potential biasing influence of mortality in this cohort by using the Fine-Gray method to calculate sub-hazard ratios (SHR) 3 , while accounting for mortality timing among 25 people who died prior to diagnosis and provided, for comparison, SHR not adjusting for death.While the SHR is not as high or as statistically significant, in general, it is similar when we adjusted for mortality as compared to when using the same method but when all deaths were censored but were not registered as competing risks.Finally, we considered the importance of using different time scales.Results supported reliance on the models that were already being reported. © 68 input exposure features and a single risk score ranging from one deemed to have high risk, to zero deemed not to be at high risk.To train the Neural network, at each epoch we split the sample into random samples made up of 80% of the sample (for training) and 20% of the sample (for testing conditions) to retain the most power possible for training purposes.Within each epoch, the neural network was presented with 1,000 training occasions and data were randomly sorted each time between occasions.The area under the receiver-operating curve was reported for the training sample, and the score was estimated for the remaining 20% of the sample and are reported in Supplemental Figure3as learning curves.When accuracy in the replication sample was reliably close (AUC≤0.10)to the training sample, the algorithm was halted, and the neural network was stored.These analyses amplified trend results among those most severely exposed in unadjusted and in multivariable-adjusted analyses such that responders with the severe but shorter exposures had elevated hazards of dementia before age 65 years, while those with severe exposures lasting ≥15 weeks had drastically elevated hazards of dementia.©2024 Clouston SAP et al.JAMA Network Open.

eFigure 2 .
Learning curves indicating the artificial neural network's ability to rely on exposure information to identify individuals with dementia in training and testing.Training is the black dashed line and 95% confidence interval; five-epoch moving average provided in red dashed lines; testing is solid black line with 95% confidence interval [gray lines]; five-epoch moving average provided in red solid line.Area under the receiver-operating curve eFigure 3. Nelson-Aalen plot and accompanying risk table showing cumulative hazards of dementia before 65 years in World Trade Center responders, stratified by probable exposure severity as determined using a combination of human and computer-driven scoring methods for probable exposures while working on-site in the aftermath of the terrorist attacks of 9/11/2001.5 2 2.5 3 3.5 4 4.5 5 Years of follow-up Low Exposure/No Dust or Wore PPE 179 159 151 128 113 103 84 33 Moderate Exposure for <15 wks 3930 3437 3197 2637 2431 1968 1532 606 Moderate Exposure for ≥15 wks 331 288 271 233 221 176 136 51 High Exposure for <15 wks 432 385 363 296 273 218 174 67 High Exposure for ≥15 wks 45 Vertical black tick marks show censoring occasions.Low-risk activities and those who were not exposed to dust or who wore full personal protection equipment always when working on-site shown in dashed navy lines.Those who completed moderately risky activities for shorter periods of time (≤15 weeks) shown in black.Those who completed moderately risky activities for lengthy periods of time (>15 weeks) shown in dashed green line.Those with severe activities for shorter periods of time (≤15 weeks) shown in yellow dashed lines.Those with severe exposure activities for lengthy periods of time (>15 weeks) shown in solid teal.Number at risk at each time-point shown in the risk table.

eFigure 4 .
Bar graph showing hazards ratios for early-onset dementia by level of exposure after adjusting for age and family history of amyotrophic lateral sclerosis, Huntington's disease, spinocerebral ataxia, or multisystem atrophy PPE Age-Adjusted Adjusted for Age and Family Risk High Risk for High Risk for activity or wore for <15 Weeks* for ≥15 weeks* <15 weeks* ≥15 weeks* Adjusted Hazards Ratio (aHR) © 2024 Clouston SAP et al.JAMA Network Open.

eFigure 1. Age-specific incidence rates stratified by five-year age group at baseline for responders in this analysis
2024 Clouston SAP et al.JAMA Network Open.Selection bias analyses showing association between all covariates and the risk of missing cognitive assessment at baseline, a second follow-up assessment, and genetic information Note: py: person-years, Incidence rates (IR) shown here are unadjusted for covariates.Age is Note: aRRs represent multivariable-adjusted risk ratios.Results are from a Poisson regression with a robust standard error.© 2024 Clouston SAP et al.JAMA Network Open.

Unadjusted and multi-variable adjusted hazard ratios examining incidence of dementia in World Trade Center responders, stratified by exposure severity
*Note: Multi-variable hazard ratios adjusted for age, gender, race/ethnicity, hypertension, diabetes, history of stroke, history of heart attack, history of head trauma, smoking status, history of heavy or binge drinking, and the propensity for the recruiter to fail to recruit participants.PPE: Personal protective equipment; py: person-years; wks: weeks on or adjacent to pile; IR: Crude Incidence Rate; HR: unadjusted hazards ratio; aHR: multivariable adjusted hazards ratio; 95% C.I.: 95% confidence interval.©2024 Clouston SAP et al.JAMA Network Open.
Sensitivity analyses showing trend-level associations between qualitative exposure metric and hazards of early-onset dementia when adjusting for additional covariates that were only available in a subset of individuals Nelson-Aalen plot and accompanying risk table showing cumulative hazards of dementia before age 65 years in minimally exposed World Trade Center responders, stratified by whether a person report no significant dust exposure or usually wore personal protective equipment as compared to those in low-risk activities while working on-site in the aftermath of the terrorist attacks of 9/11/2001 2024 Clouston SAP et al.JAMA Network Open.eTable 3.Note: *Reports a demographically adjusted SHR (Subhazard Ratio) using the Fine-Gray method.COVID-19: Coronavirus Disease of 2019, aHR: demographically adjusted hazards ratio; 95% CI: 95% confidence interval; P: P-value.